Beta-amino acid derivatives for treatment of diabetes

ABSTRACT

Novel heterocyclic compounds of the formula I 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , R 2′ , R 2″ , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the meanings indicated in Claim  1,  
 
are activators of glucokinase and can be used for the prevention and/or treatment of Diabetes Typ 1 and 2, obesity, neuropathy and/or nephropathy.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds that are useful in thetreatment and/or prevention of diseases mediated by deficient levels ofglucokinase activity, such as diabetes mellitus, and methods ofpreparing such compounds. Also provided are methods of treating diseasesand disorders characterized by underactivation of glucokinase activityor which can be treated by activating glucokinase, comprisingadministering an effective amount of a compound of this invention.

The identification of small compounds which specifically activate,regulate and/or modulate signal transduction of glucokinase is thereforedesirable and an aim of the present invention. Moreover, aim of thisinvention was the preparation of new compounds for the prevention and/ortreatment of Diabetes Type 1 and 2, obesity, neuropathy and/ornephropathy.

Surprisingly we have found that β-amino acid derivatives activateglucokinase; therefore, these compounds are especially suitable for theprevention and treatment of Diabetes Type 1 and 2, obesity, neuropathyand/or nephropathy, it has been found that the compounds according tothe invention and salts thereof have very valuable pharmacologicalproperties while being well tolerated.

In particular, they exhibit glucokinase activating effects.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesand also to a process for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

The host or patient may belong to any mammal species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

Diabetes mellitus (DM) is a progressive disease often associated withobesity characterized by insulin deficiency and insulin resistance orboth. The fasting and post-prandial blood glucose is elevated, exposingthe patient to acute and chronic complications (micro- andmacro-vascular) leading to blindness, kidney failure, heart disease,stroke and amputations. Improving glycemic control has been demonstratedto lower the risk of these complications. Owing to the progressivenature of the disease, an evolving treatment strategy is necessary tomaintain glycemic control. There are two forms of diabetes mellitus:type 1, or juvenile diabetes or insulin-dependent diabetes mellitus(IDDM), and type 2, or adult-onset diabetes or non insulin-dependentdiabetes mellitus (NIDDM). Type 1 diabetes patients have an absoluteinsulin insufficiency due to the immunological destruction of pancreaticβ cells that synthesize and secrete insulin. Type 2 diabetes is morecomplex in etiology and is characterized by a relative insulindeficiency, reduced insulin action, and insulin resistance. Early-onsetNIDDM or maturity-onset diabetes of the young (MODY) shares manyfeatures of the most common form of NIDDM whose onset occurs in themidlife (Rotter et al 1990). A clear mode of inheritance (autosomaldominant) has been observed for MODY. At least, 3 distinct mutationshave been identified in MODY families (Bell et al. 1996). The importanceof Glucokinase (GK) in glucose homeostasis has been demonstrated by theassociation of GK mutants with diabetes mellitus in humans (MODY-2) andby alteration in glucose metabolism in transgenic mice and geneknock-out mice (Froguel et al. 2003; Bali et al. 1995, Postic et al.1999).

GK, also known as hexokinase IV or D, is one of four hexokinase isozymesthat metabolize glucose to glucose 6-phosphate [Wilson, 2004]. GK isknown to be expressed in neural/neuroendocrine cells, hepatocytes andpancreatic cells and plays a central role in whole body homeostasis[Matschinsky et al. 1996; 2004]. GK plays an important role as a glucosesensor for controlling plasma glucose homeostasis by enhancing insulinsecretion from pancreatic β-cells and glucose metabolism in the liverbut also by increasing GLP1 secretion from L-Cells. β-cells,glucose-sensing in the arcuate (ARC) hypothalamic nucleus may depend onGK to detect a rise in glucose and facilitate glucose-induced-insulinsecretion.

The multiple mechanism of action suggests that GK activators will exerttheir biological effects in diabetic and obese patients by improving theoverall body glucose awareness which provides rational expectations thatenhancement of GK activity would be a novel therapeutic strategy formetabolic disorders. It is anticipated that GK activators will restoreappropriated pancreatic hormones and incretin secretion coupled with asuppression of hepatic glucose production without inducing severehypoglycemia.

PRIOR ART

Other glucokinase activators are disclosed in WO 02/48106, WO2003/055482, WO 2004/034962 as well as in WO 03/015774 A1, EP 1 420 784B1, WO 2005/080359 A1, WO 2005/080360 A1, WO 2005/121110, WO2006/040527, WO 2006/040528, WO 2006/040529, WO 2006/125972, WO2007/007040, WO 2007/007041, WO 2007/007042, WO 2007/017649.

BIBLIOGRAPHY

-   Wilson J E: The hexokinase gene family. In Glucokinase and Glycemic    Disease: From Basics to Novel Therapeutics. Front Diabetes. Vol. 16.-   Matschinsky F M, Magnuson M A, Eds. Basel, Karger, 2004-   Matschinsky, F. M. Diabetes 1996, 45, 223-41.-   Matschinsky F. M.; Magnuson M. A. eds. Glucokinase and Glycemic    Disease: From Basics to Novel Therapeutics. Basel:Karger, 2004-   Rotter et al. Diabetes mellitus (1990): Theory and practice Rifkin    and Porte (Eds) NY, 378-413-   Bell et al 1996-   Froguel et al. 2003-   Bali et al. 1995-   Postic et al. 1999

Following β-amino acid derivatives are described together with their CASnumbers in a catalogue for chemicals without any further information

-   N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B1”; CAS 894237-57-1),-   N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B2”; CAS 894231-45-9),-   3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide    (“B3”; CAS 894226-60-9),-   3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B4”; CAS 894231-94-8),-   N-(5-Bromo-pyridine-2-yl)-3-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B5”; CAS 894230-41-2),-   N-(5-Chloro-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B6”; CAS 894226-18-7),-   N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B7”; CAS 894231-80-2),-   N-(5-Chloro-pyridine-2-yl)-3-(4-fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)propionamide    (“B8”; CAS 894250-11-4),-   3-(3,4-Dimethoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B9”; CAS 894226-48-3),-   N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide    (“B10”; CAS 894240-23-4),-   3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridin-2-yl-3-thiophene-2-yl-propionamide    (“B11”; CAS 894252-13-2),-   3-(4-Methoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B12”; CAS 894246-50-5),-   N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B13”; CAS 894231-87-9),-   3-(4-Methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B14”; CAS 894248-37-4),-   3-(3,4-Dimethoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B15”; CAS 894226-54-1),-   3-(4-Methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B16”; CAS 894246-43-6),-   3-(4-Methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide    (“B17”; CAS 894246-57-2),-   N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B18”; CAS 894231-66-4),-   3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B19”; CAS 894235-27-9).

These compounds are disclaimed from the compound claims.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes A, Ar or Het,-   R², R^(2′), R^(2″) each, independently of one another, denote H, A,    OA or Hal,-   R³ denotes Het,-   R⁴, R⁵ denote H,-   R⁶ denotes H, A, Ar or Het,-   R⁷, R⁸ denote H or    -   R⁷ and R⁸ together denote ═O,-   R⁹, R¹⁰, R¹¹ each, independently of one another, denote H, A, Ar or    Het,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    one or two non-adjacent CH₂ groups may be replaced by O, S, SO, SO₂,    NH, NA′, NAr, NHet and/or by —CH═CH— groups and/or in addition 1-7 H    atoms may be replaced by OH, F, Cl, Br, ═S, ═NR⁹ and/or ═O    -   or    -   denotes cycloalkyl having 3-7 C atoms, which is unsubstituted or        mono-, di- or trisubstituted by ═O, F, Cl, OH, OA′, OAr′, OHet′,        SO_(n)A′, SO_(n)Ar′, SO_(n)Het′, NH₂, NHA′, NA′₂, NHAr′ and/or        NHHet′,-   A′ denotes unbranched or branched alkyl having 1-6 C atoms in which    1-7 H atoms may be replaced by F and/or Cl,-   Alk denotes unbranched or branched alkylene having 1, 2, 3 or 4 C    atoms,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A,    Hal, (CR⁹R¹⁰)_(m)Ar′, (CR⁹R¹⁰)_(m)Het′, O(CR⁹R¹⁰)_(m)R¹¹,    S(O)_(n)R⁹, NH₂, NHA′, NA′₂, NHAr′, NHHet′, NO₂, CN, COOR⁹,    CON(R⁹R¹⁰)₂, NR⁹COR¹⁰, NR⁹CON(R¹⁰R¹¹)₂, NR⁹SO_(n)R¹⁰, COR⁹, SO₃H,    SO_(n)N(R⁹R¹⁰)₂, O-Alk-N(R⁹R¹⁰)₂, O(CR⁹R¹⁰)_(m)CON(R⁹R¹⁰)₂,    O-Alk-NR⁹COR¹⁰, O(CR⁹R¹⁰)_(m)Het′, O(CR⁹R¹⁰)_(m)Ar′,    S(O)_(n)(CR⁹R¹⁰)_(m)Het′ and/or S(O)_(n)(CR⁹R¹⁰)_(m)Ar′,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A, (CR⁹R¹⁰)_(m)Ar′, (CR⁹R¹⁰)_(m)Het′,    O(CR⁹R¹⁰)_(m)Ar′, O(CR⁹R¹⁰)_(m)Het′,    -   (CR⁹R¹⁰)_(m)cycloalkyl, (CR⁹R¹⁰)_(m)OR¹², (CR⁹R¹⁰)_(m)N(R¹¹)₂,        NO₂) CN, (CR⁹R¹⁰)_(m)COOR¹¹, O(CR⁹R¹⁰)_(m)COOR¹¹,        (CR⁹R¹⁰)_(m)CON(R¹¹)₂, (CR⁹R¹⁰)_(m)CONR¹¹N(R⁹R¹⁰)₂,        O(CR⁹R¹⁰)_(m)CON(R¹¹)₂, O(CR⁹R¹⁰)_(m)CONR¹¹N(R⁹R¹⁰)₂,        (CR⁹R¹⁰)_(m)NR¹¹COA, NR⁹CON(R¹⁰R¹¹)₂, (CR⁹R¹⁰)_(m)NR¹¹SO₂A,        COR⁹, SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, ═S, ═NR² and/or ═O (carbonyl        oxygen),-   Ar′ denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A, OR⁹,    N(R⁹R¹⁰)₂, NO₂, CN, COOR⁹, CON(R⁹R¹⁰)₂, NR⁹COA, NR⁹CON(R¹⁰R¹¹)₂,    NR⁹SO₂A, COR⁹, SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, (CR⁹R¹⁰)_(m)COOR¹¹ and/or    O(CR⁹R¹⁰)_(m)COOR¹¹,-   Het′ denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A, OR⁹, N(R⁹R¹⁰)₂, NO₂, CN, COOR⁹,    CON(R⁹R¹⁰)₂, NR⁹COA, NR⁹SO₂A, COR⁹, SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, ═S,    ═NR⁹ and/or ═O (carbonyl oxygen),-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1, 2, 3 or 4,-   n denotes 0, 1 or 2,    and pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios,    excluding the compounds selected from the group-   N-(5-Bromo-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,-   N-(5-Chloro-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,-   3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-propionamide,-   3-(1-Oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide,-   N-(5-Bromo-pyridin-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   N-(5-Chloro-pyridin-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   N-(5-Methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,-   N-(5-Chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   3-(3,4-Dimethoxy-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   N-(5-Bromo-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-3-p-tolyl-propionamide,-   3-(1-Oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-3-thiophen-2-yl-propionamide,-   3-(4-Methoxy-phenyl)-N-(6-methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   N-(6-Methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,-   3-(4-Methoxy-phenyl)-N-(4-methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   3-(3,4-Dimethoxy-phenyl)-N-(6-methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   3-(4-Methoxy-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,-   3-(4-Methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-propionamide,-   N-(4-Methyl-thiazol-2-yl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,-   3-(1-Oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-3-(2,4,5-trimethoxy-phenyl)-propionamide.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to Claims 1-21 and pharmaceutically usable salts andstereoisomers thereof, characterised in that

a compound of the formula II

-   -   in which    -   L denotes Cl, Br, I or a free or reactively functionally        modified OH group and    -   R¹, R², R^(2′), R^(2″), R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings        indicated in Claim 1,        is reacted with a compound of the formula III

H₂N—R³  III

-   -   in which R³ has the meanings indicated in Claim 1,        and/or        a base or acid of the formula I is converted into one of its        salts.

The invention also relates to the stereoisomers (including E, Z isomers)and the hydrates and solvates of these compounds. Solvates of thecompounds are taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.

Compounds of formula I also mean their tautomers, solvates and theirpharmaceutically usable derivatives.

Pharmaceutically usable derivatives is taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives is taken to mean compounds of the formula I whichhave been modified, with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to form theactive compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as is described, for example, in Int. J.Pharm. 115, 61-67 (1995).

The expression “effective amount” means the amount of a medicament orpharmaceutical active ingredient which causes a biological or medicalresponse which is sought or aimed at, for example by a researcher orphysician, in a tissue, system, animal or human.

In addition, the expression “therapeutically effective amount” means anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or prevention of side effectsor also the reduction in the progress of a disease, condition, disorderor side effects or also the reduction in the progress of a disease,condition or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals and parameters R¹, R², R³, R⁴ and D havethe meanings indicated for the formula I, unless expressly indicatedotherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-tri-methylpropyl, further preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl. Moreover, A preferably denotes unbranched orbranched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replacedby OH, F and/or Cl. Cycloalkyl preferably denotes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Alk preferably denotes CH₂ oder CH₂CH₂.

R¹ preferably denotes Ar or Het. R¹ denotes particularly preferablyphenyl, which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by A, Hal and/or OA; R¹ further denotes particularlypreferably pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl,furanyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, benzo[1,3]dioxolyl, benzimidazolyl,benzo[1,2,5]thiadiazolyl, indolyl or indazolyl.

R², R^(2′), R^(2″) preferably denote H.R⁶, R⁷, R⁸, R⁹, R¹⁰ preferably denote H.R¹¹ preferably denotes H or A, particularly preferably H, methyl, ethyl,propyl, isopropyl or butyl.m preferably denotes 0 or 1.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxy-phenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethyl-amino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluoro-phenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl,o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m- orp-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodo-phenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes phenyl, which is unsubstituted or mono-, di-,tri-, tetra- or pentasubstituted by A, Hal and/or O(CR⁹R¹⁰)_(m)R¹¹.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-innolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl,5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or fully hydrogenated.

Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or 5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzo-furanyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a mono- or bicyclic unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may be mono-, di-or trisubstituted by Hal, A and/or (CR⁹R¹⁰).

Het particularly preferably denotes pyrazolyl, imidazolyl, triazolyl,tetrazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzo[1,3]dioxolyl,benzimidazolyl, benzo[1,2,5]thiadiazolyl, indolyl, indazolyl, which maybe mono-, di- or trisubstituted by Hal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ik, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes Ar or Het;-   in Ib R², R^(2′), R^(2″) denote H;-   in Ic R⁶ denotes H;-   in Id R⁷, R⁸ denote H;-   in Ie R⁹, R¹⁰ denote H;-   in If R¹¹ denotes H or A;-   in Ig A denotes unbranched or branched alkyl having 1-10 C atoms, in    which 1-7 H atoms may be replaced by F and/or Cl;-   in Ih Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,    tetra- or pentasubstituted by A, Hal and/or O(CR⁹R¹⁰)_(m)R¹¹;-   in Ii Het denotes a mono- or bicyclic unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹;-   in Ij Het denotes pyrazolyl, imidazolyl, triazolyl, tetrazolyl,    pyrrolyl, furanyl, thienyl, thiazolyl, pyridyl, pyrazinyl,    pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzo[1,3]dioxolyl,    benzimidazolyl, benzo[1,2,5]thiadiazolyl, indolyl, indazolyl, which    may be mono-, di- or trisubstituted by Hal, A and/or    (CR⁹R¹⁰)_(m)COOR¹¹;-   in Ik R¹ denotes Ar or Het,    -   R², R^(2′), R^(2″) denote H,    -   R³ denotes Het,    -   R⁴, R⁵ denote H,    -   R⁶ denotes H,    -   R⁷, R⁸ denote H,    -   R⁹, R¹⁰ denote H,    -   R¹¹ denotes H or A,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl,    -   Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted by A, Hal and/or O(CR⁹R¹⁰)_(m)R¹¹,    -   Het denotes a mono- or bicyclic unsaturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        mono-, di- or trisubstituted by Hal, A and/or        (CR⁹R¹⁰)_(m)COOR¹¹,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1, 2, 3 or 4;        and pharmaceutically usable salts and stereoisomers thereof,        including mixtures thereof in all ratios.

The compounds according to the invention and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se, which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds according to theinvention.

The starting compounds are generally known. If they are novel, however,they can be prepared by methods known per se.

Compounds of the formula I, can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

The reaction is carried out by methods which are known to the personskilled in the art.

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an alkali oralkaline-earth metal hydroxide, carbonate or bicarbonate or another saltof a weak acid of the alkali or alkaline-earth metals, preferably ofpotassium, sodium, calcium or caesium. The addition of an organic base,such as triethylamine, dimethylaniline, pyridine or quinoline may alsobe favourable.

The starting substances of the formulae II and III are known in somecases. If they are not known, they can be prepared by methods known perse.

In the compounds of the formula II, L is preferably Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).

Activated esters are advantageously formed in situ, for example throughaddition of HOBt or N-hydroxysuccinimide.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 110°, in particular between about 20°and about 100°.

Other radicals can be converted by reducing nitro groups (for example byhydrogenation on Raney nickel or Pd/carbon in an inert solvent, such asmethanol or ethanol) to amino groups or hydrolysing cyano groups to COOHgroups.

Furthermore, free amino groups can be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30° C.

Ester groups can be saponified, for example, using NaOH or KOH in water,water/THF or water/dioxane at temperatures between 0 and 100° C.Carboxylic acids can be converted, for example using thionyl chloride,into the corresponding carboxylic acid chlorides, and the latter can beconverted into carboxamides. Elimination of water therefrom in a knownmanner gives carbonitriles.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphor-sulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentane-propionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecyl-sulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzyl-ethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethyl-amine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethyl-amine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usable saltsand stereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using alt processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The compounds according to the inventioncan also be combined with a free-flowing inert excipient and thenpressed directly to give tablets without carrying out the granulation ordry-pressing steps. A transparent or opaque protective layer consistingof a shellac sealing layer, a layer of sugar or polymer material and agloss layer of wax may be present. Dyes can be added to these coatingsin order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compounds. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emuisifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds according to the invention and salts, solvates andphysiologically functional derivatives thereof can also be administeredin the form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours. A therapeutically effective amountof a compound of the present invention depends on a number of factors,including, for example, the age and weight of the human or animal, theprecise disease condition which requires treatment, and its severity,the nature of the formulation and the method of administration, and isultimately determined by the treating doctor or vet. However, aneffective amount of a compound according to the invention is generallyin the range from 0.1 to 100 mg/kg of body weight of the recipient(mammal) per day and particularly typically in the range from 1 to 10mg/kg of body weight per day. Thus, the actual amount per day for anadult mammal weighing 70 kg is usually between 70 and 700 mg, where thisamount can be administered as an individual dose per day or usually in aseries of part-doses (such as, for example, two, three, four, five orsix) per day, so that the total daily dose is the same. An effectiveamount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usable saltsand stereoisomers thereof, including mixtures thereof in all ratios, andat least one further medicament active ingredient.

Moreover the invention relates to medicaments comprising at least onecompound selected from the group

-   N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B1”; CAS 894237-57-1),-   N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B2”; CAS 894231-45-9),-   3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide    (“B3”; CAS 894226-60-9),-   3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B4”; CAS 894231-94-8),-   N-(5-Bromo-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B5”; CAS 894230-41-2),-   N-(5-Chloro-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B6”; CAS 894226-18-7),-   N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B7”; CAS 894231-80-2),-   N-(5-Chloro-pyridine-2-yl)-3-(4-fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B8”; CAS 894250-11-4),-   3-(3,4-Dimethoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B9”; CAS 894226-48-3),-   N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide    (“B10”; CAS 894240-23-4),-   3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridin-2-yl-3-thiophene-yl-propionamide    (“B11”; CAS 894252-13-2),-   3-(4-Methoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B12”; CAS 894246-50-5),-   N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)propionamide    (“B13”; CAS 894231-87-9),-   3-(4-Methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B14”; CAS 894248-37-4),-   3-(3,4-Dimethoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B15”; CAS 894226-54-1),-   3-(4-Methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide    (“B16”; CAS 894246-43-6),-   3-(4-Methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide    (“B17”; CAS 894246-57-2),-   N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B18”; CAS 894231-66-4),-   3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide    (“B19”; CAS 894235-27-9).

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound according to the invention    and/or pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, in particular for humans, in the treatment of Diabetes Type1 and 2, obesity, neuropathy and/or nephropathy.

The invention thus relates to the use of compounds according to Claim 1and to pharmaceutically usable salts and stereoisomers, includingmixtures thereof in all ratios, for the preparation of a medicament forthe treatment of Diabetes Type 1 and 2, obesity, neuropathy and/ornephropathy.

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases or disorders mediated bydeficient levels of glucokinase activity or which can be treated byactivating glucokinase including, but not limited to, diabetes mellitus,impaired glucose tolerance, IFG (impaired fasting glucose) and IFG(impaired fasting glycemia), as well as other diseases and disorderssuch as those discussed below.

Furthermore, the compounds of the present invention can be also used toprevent the progression of the borderline type, impaired glucosetolerance, IFG (impaired fasting glucose) or IFG (impaired fastingglycemia) to diabetes mellitus.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents of diabetic complications such as, but not limitedto, neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma), infectious diseases (e.g.,respiratory infection, urinary tract infection, gastrointestinal tractinfection, dermal soft tissue infection, lower limb infection etc.),diabetic gangrene, xerostomia, decreased sense of hearing,cerebrovascular disease, peripheral circulatory disturbance, etc.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, obesity, metabolic syndrome (syndrome X),hyperinsulinemia, hyperinsulinemia-induced sensory disorder,dyslipoproteinemia (abnormal lipoproteins in the blood) includingdiabetic dyslipidemia, hyperlipidemia, hyperlipoproteinemia (excess oflipoproteins in the blood) including type I, II-a(hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V(hypertriglyceridemia), low HDL levels, high LDL levels, atherosclerosisand its sequelae, vascular restenosis, neurodegenerative disease,depression, CNS disorders, liver steatosis, osteoporosis, hypertension,renal diseases (e.g., diabetic nephropathy, glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,terminal renal disorder etc.), myocardiac infarction, angina pectoris,and cerebrovascular disease (e.g., cerebral infarction, cerebralapoplexy).

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, osteoporosis, fatty liver, hypertension, insulinresistant syndrome, inflammatory diseases (e.g., chronic rheumatoidarthritis, spondylitis deformans, osteoarthritis, lumbago, gout,postoperative or traumatic inflammation, remission of swelling,neuralgia, pharyngolaryngitis, cystitis, hepatitis (includingnon-alcoholic steatohepatitis), pneumonia, inflammatory colitis,ulcerative colitis), pancreatitis, visceral obesity syndrome, cachexia(e.g., carcinomatous eachexia, tuberculous cachexia, diabetic cachexia,hemopathic cachexia, endocrinopathic cachexia, infectious cachexia,cachexia induced by acquired immunodeficiency syndrome), polycysticovary syndrome, muscular dystrophy, tumor (e.g., leukemia, breastcancer, prostate cancer, skin cancer etc.), irritable bowel syndrome,acute or chronic diarrhea, spondylitis deformans, osteoarthritis,remission of swelling, neuralgia, pharyngolaryngitis, cystitis, SIDS,and the like.

The compounds of the present invention can be used in combination withone or more additional drugs such as described below. The dose of thesecond drug can be appropriately selected based oh a clinically employeddose. The proportion of the compound of formula I and the second drugcan be appropriately determined according to the administration subject,the administration route, the target disease, the clinical condition,the combination, and other factors. In cases where the administrationsubject is a human, for instance, the second drug may be used in anamount of 0.01 to 100 parts by weight per part by weight of the compoundof formula I.

The second compound of the pharmaceutical combination formulation ordosing regimen preferably has complementary activities to the compoundof formula I such that they do not adversely affect each other. Suchdrugs are suitably present in combination in amounts that are effectivefor the purpose intended. Accordingly, another aspect of the presentinvention provides a composition comprising a compound of formula I, ora solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, in combination with a second drug, such as described herein.

The compound of formula I and the additional pharmaceutically activeagent(s) may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time. The amounts ofthe compound of formula I and the second agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect. The combination therapy may provide“synergy” and prove “synergistic”, i.e., the effect achieved when theactive ingredients used together is greater than the sum of the effectsthat results from using the compounds separately. A synergistic effectmay be attained when the active ingredients are: (1) co-formulated andadministered or delivered simultaneously in a combined, unit dosageformulation; (2) delivered by alternation or in parallel as separateformulations; or (3) by some other regimen. When delivered inalternation therapy, a synergistic effect may be attained when thecompounds are administered or delivered sequentially, e.g., by differentinjections in separate syringes. In general, during alternation therapy,an effective dosage of each active ingredient is administeredsequentially, i.e., serially, whereas in combination therapy, effectivedosages of two or more active ingredients are administered together.

The compounds of the present invention can be used, for example incombination with additional drug(s) such as a therapeutic agent fordiabetes mellitus, and/or a therapeutic agent for diabeticcomplications, as defined above.

Examples of known therapeutic agents for diabetes mellitus which can beused in combination with a compound of formula I include insulinpreparations (e.g., animal insulin preparations extracted from thebovine or swine pancreas; human insulin preparations synthesized by agenetic engineering technique using Escherichia coli or a yeast), afragment of insulin or derivatives thereof (e.g., INS-i), agents forimproving insulin resistance (e.g., pioglitazone hydrochloride,troglitazone, rosiglitazone or its maleate, GI-262570, JTT-50 1,MCC-555, YM-440, KRP-297, CS-Oil, FK-614), alpha-glucosidase inhibitors(e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g.,phenformin, metformin, buformin), insulin secretagogues [sulfonylureas(e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide,tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide,glybuzole), repaglinide, nateglinide, mitiglinide or its calcium salthydrate, GLP-1J, dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278,PT-100), beta-3 agonists (e.g., CL-3 16243, SR-58611-A, UL-TG-307,SB-226552, AJ-9677, BMS-I96085, AZ-40140, etc.), amylin agonists (e.g.,pramlintide), phosphotyrosine phosphatase inhibitors (e.g., vanadicacid), gluconeogenesis inhibitors (e.g., glycogen phosphorylaseinhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists),SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095), and thelike. Examples of known therapeutic agents for diabetic complicationsinclude aldose reductase inhibitors (e.g., tolrestat, epairestat,zenarestat, zopobestat, minairestat, fidarestat (SNK-860), CT-i 12),neurotrophic factors (e.g., NGF, NT-3, BDNF), neurotrophic factorproduction secretion promoters, PKC inhibitors (e.g., LY-333531), AGEinhibitors (e.g., ALT946, pimagedine, pyratoxathine,N-phenacylthiazolium bromide (ALT766), EXO-226), active oxygenscavengers (e.g., thioctic acid), and cerebral vasodilators (e.g.,tiapuride, mexiletine).

The compounds of the present invention can also be used, for example incombination with antihyperlipidemic agents. Epidemiological evidence hasfirmly established hyperlipidemia as a primary risk factor in causingcardiovascular disease (CVD) due to atherosclerosis. In recent years,emphasis has been placed on lowering plasma cholesterol levels, and lowdensity lipoprotein cholesterol in particular, as an essential step inprevention of CVD.

Cardiovascular disease is especially prevalent among diabetic subjects,at least in part because of the existence of multiple independent riskfactors in this population. Successful treatment of hyperlipidemia inthe general population, and in diabetic subjects in particular, istherefore of exceptional medical importance. Examples ofantihyperlipidemic agents include statin compounds which are cholesterolsynthesis inhibitors (e.g., cerivastatin, pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, itavastatin or their salts,etc.), squalene synthase inhibitors or fibrate compounds (e.g.,bezafibrate, clofibrate, simfibrate, clinofibrate) having a triglyceridelowering action and the like.

The compounds of the present invention can also be used, for example incombination with hypotensive agents. Hypertension has been associatedwith elevated blood insulin levels, a condition known ashyperinsulinemia. Insulin, a peptide hormone whose primary actions areto promote glucose utilization, protein synthesis and the formation andstorage of neutral lipids, also acts to promote vascular cell growth andincrease renal sodium retention, among other things. These latterfunctions can be accomplished without affecting glucose levels and areknown causes of hypertension. Peripheral vasculature growth, forexample, can cause constriction of peripheral capillaries, while sodiumretention increases blood volume. Thus, the lowering of insulin levelsin hyperinsulinemics can prevent abnormal vascular growth and renalsodium retention caused by high insulin levels and thereby alleviateshypertension. Examples of hypotensive agents include angiotensinconverting enzyme inhibitors (e.g., captopril, enalapril, delapril),angiotensin II antagonists (e.g., candesartan cilexetil, losartan,eprosartan, valsantan, termisartan, irbesartan, tasosartan), calciumantagonists (e.g., manidipine, nifedipine, nicardipine, amlodipine,efonidipine), and clonidine.

The compounds of the present invention can be used in combination withantiobesity agents. The term “obesity” implies an excess of adiposetissue. Obesity is a well-known risk factor for the development of manyvery common diseases such as diabetes, atherosclerosis, andhypertension. To some extent appetite is controlled by discrete areas inthe hypothalamus: a feeding centre in the ventrolateral nucleus of thehypothalamus (VLH) and a satiety centre in the ventromedial hypothalamus(VMH). The cerebral cortex receives positive signals from the feedingcenter that stimulate eating, and the satiety center modulates thisprocess by sending inhibitory impulses to the feeding center. Severalregulatory processes may influence these hypothalamic centers. Thesatiety center may be activated by the increases in plasma glucoseand/or insulin that follow a meal. Examples of antiobesity agentsinclude antiobesity drugs acting on the central nervous system (e.g.,dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon,dexamphetamine, mazindol, phenylpropanolamine, clobenzorex), pancreaticlipase inhibitors (e.g. orlistat), beta-3 agonists (e.g., CL-3 16243,SR-5861 1-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140),anorectic peptides (e.g., leptin, CNTF (Ciliary Neurotrophic Factor) andcholecystokinin agonists (e.g. lintitript, FPL-1 5849).

Assays Glucokinase Activation Screening Assay

GK activity (human or rat enzyme) is measured by a coupled enzyme assayusing pyruvate kinase (PK) and lactate dehydrogenase (LDH) as couplingenzymes. GK activity is calculated from the decline in NADH monitoredphotometrically with a microtiter plate (MTP) reader at 340 nm.

For screening purposes, the GK assay is routinely run in a 384-MTPformat, in a total volume of 33 μl/well. 10 μl of the ATP-regenerationsolution (in HEPES-buffer*, pH 7.0, 6.73 U/ml pyruvate kinase, 6.8 U/mllactate dehydrogenase) and 10 μl of the glucokinase-/glucose solution(15 μg/ml, 6.6 mM glucose in HEPES-buffer*, pH 7.0; the concentration ofthe glucose stock-solution was 660 mM in Millipore H₂O) were mixedtogether with 3 μl of a 10% DMSO solution (in HEPES-buffer*, pH 7.0)containing 3.3-fold the amounts of the compounds to achieve finalcompound concentrations in the range between 1 nM to 30 μM (sometimes300 μM) in the assay solution (s. below). The solutions were mixed for 5sec, and after a centrifugation at 243×g for 5 min, the solutions werepreincubated for 25 min at room temperature. The reaction was started bythe addition of 10 μl of the NADH-/ATP-solution (4.29 mM NADH, 4.95 mMATP, in HEPES-buffer*). The MTP was shaken for 5 sec., and then, theabsorbance at 340 nm was monitored continuously in a MTP-reader (TECANSpectro fluor plus) for the next 27 min (with a MTP-cycling time of 199sec.). The final concentrations of the various components were asfollows: 49.5 mM Hepes, pH 7.0, 1.49 mM PEP, 1.3 mM NADH, 49.5 mM KCl,4.96 mM MgCl₂, 1.5 mM Mg-ATP, 1.98 mM DTT, 2.04 U/ml pyruvate kinase,2.06 U/ml lactate-dehydrogenase, 0.91% DMSO, 0.15 μg/well glucokinase,and test compounds in the range between 1 nM and 300 μM, The change inthe optical density (ΔOD_(340 nm)) in the presence of the compound wasexpressed relative to the ΔOD_(340 nm, ctrl) of the control incubation(in the presence of 2 mM glucose and 0.91% DMSO), taking into accountthe optical density of the blank sample (incubation in the absence of 2mM glucose). For the determination of the half maximal effectiveconcentration (EC₅₀), the %-Ctrl-values were plotted in asemi-logarithmic graph against the cone. of the compound of interest.The data points were fitted to a sigmoid curve function(f(x)=((%-Ctrl_(max)−%-Ctrl_(min))/(1−(EC₅₀/x**^(n(Hill))))+%-Ctrl_(min)))by a non-linear regression analysis.

-   -   Hepes-buffer (50 mM Hepes, pH 7.0, 5 mM MgCl₂, 50 mM KCl, 1.5 mM        PEP, 0.1% BSA). DTT was added to the Hepes-buffer from a 200×        stock solution (in Millipore H₂O) freshly each day. The final        concentration of DTT in the Hepes-buffer is 2 mM.

Culture of Pancreatic INS-1 Cells

INS-1 cells were cultured in complete medium, RPMI1640 containing 1 mMsodium pyruvate, 50 μM 2-mercaptoethanol, 2 mM glutamine, 10 mM HEPES,100 IU/mL penicillin, and 100 μg/mL streptomycin (CM), supplemented with10 mM glucose, and 10% (vol/vol) heat-inactivated fetal calf serum(FCS), as described by Asfari et al. (Endocrinology 130:167-178, 1992).

Insulin Secretion Assay

INS-1 cells were plated and cultured in 48-well plates. After 2 days ofculture, the medium was removed and cells were cultured for 24 h with amedium change to 5 mM glucose, 1% FCS. The cells were then washed withKrebs-Ringer Bicarbonate HEPES buffer (KRBH; 135 mM NaCl; 3.6 mM KCl; 5mM NaHCO3; 0.5 mM NaH2PO4; 0.5 mM MgCl2; 1.5 mM CaCl2 and 10 mM HEPES;pH 7.4) 0.1% BSA containing 2.8 mM glucose and preincubated for 30 minat 37° C. in the same buffer. The cells were then washed twice andincubated for 1 h in KRBH 0.1% BSA containing 2.8 or 4.2 mM glucose anddifferent concentrations of the tested molecule. Insulin concentrationin the collected supernatants was measured with ELISA using rat insulinantibody (Insulin Rat Elit PLUS, cat. ref 10-1145-01).

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other glucokinase activators of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention may be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interfering groups, by utilizing othersuitable reagents known in the art other than those described, and/or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: if necessary, water is added,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or di-chloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisatton) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺ (unless indicated        otherwise)        Melting Points (mp.): melting points are determined with a BÜCHI        Melting Point B-540

LC-MS-Conditions

Mass data (MH⁺, given as m/z values) were taken from LC-MS measurementsand were recorded with a Hewlett Packard System of the HP 1100 serieswith an ELS-detector Sedex 75 from ERC with the followingcharacteristics: Ion source: Electrospray (positive mode); Scan:100-1000 m/z; Fragmentation-voltage: 60 V; Gas-temperature: 300° C.,DAD: 220 nm.

Flow rate: 2.4 ml/Min. The used splitter reduced the flow rate after theDAD for the MS to 0.75 ml/Min.

Column: Chromolith Speed ROD RP-18e 50-4.6 Solvent: LiChrosolv (MerckKGaA) Solvent A: H2O (0.01% TFA) Solvent B: ACN (0.01% TFA)

Method A: In 2.6 min from 96% A to 100% B. Followed by 0.7 min 100% B.

SFC-Conditions for Enantiomer Separation

Berger SFC™ Minigram (tubing: preparative mode)column: Chiralpak AS-H (Daicel), 5 μm, 4.6 mm×250 mmeluent: method A: 85% CO₂/15% MeOH; method B: 70% CO₂/30% MeOHflow: 5 ml/minoutlet pressure: 100 barcolumn temperature: 35° C.

UV: 250 nm

preparative injections: method A: 100 μl of a 4 mg/ml ACN/MeOH (1:1)solution;method B: 100 μl of a 5 mg/ml ACN/MeOH (3:2) solution

EXAMPLE 1 Preparation of3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide(“A1”)

Step A: Benzaldehyde (6 mmol, 1 eq), 2-methyl-propane-2-sulfinic acidamide (1 eq) and tetraethyl orthotitanate (3 eq) are dissolved inanhydrous THF under nitrogen (J. Org. Chem. 2003, 68, 9948-9957). Themixture is stirred at room temperature over night. The mixture is pouredin brine and stirred vigorously. The resulting suspension is filteredthrough Celite and the filter cake is extracted with ethyl acetate. Thefiltrate is transferred to a separatory funnel, where the aqueous layeris separated and extracted 3× with ethyl acetate. The organic layers arecombined, washed with brine, dried over Na₂SO₄ and concentrated invacuo. Tert.-butane-sulfinic acid 1-phenyl-methylidene amide is obtainedas a clear yellowish oil (90% yield); ES-MS (MH⁺)=210.2; ¹H-NMR(DMSO-d₆, 400 MHz): δ [ppm] 8.56 (s, 1H), 7.96-7.93 (m, 2H), 7.63-7.53(m, 3H), 1.19 (s, 9H).

Step B: Under anhydrous conditions a solution of i-Pr2NH (2.2 eq) in 60mL THF is cooled to 0° C. (J. Org. Chem. 2003, 68, 9948-9957). n-BuLi(2.1 eq, 1.6 M solution in hexane) is added via syringe and the solutionis stirred for 30 min. The solution is then cooled to −78° C. A solutionof acetic acid methyl ester (2 eq) in 1 mL of THF is added via syringeand the reaction solution is stirred for 30 min. To this solution isadded ClTi(Oi-Pr)₃ (4.2 eq) in 20 mL THF and the solution is stirred for30 min. A solution of the tert.-butane-sulfinic acid1-phenyl-methylidene amide (5.4 mmol, 1 eq) in 5 mL THF is slowly addedvia syringe and the solution is stirred for 3 h at −78° C. Upon reactioncompletion as determined by TLC, a saturated aqueous solution of NH₄Cl(5 mL) is added and the suspension is warmed to room temperature. Themixture is diluted with H₂O and vigorously stirred to dissolve theprecipitate. The mixture is then decanted into a separatory funnel, andthe remaining solid is diluted with equal parts of H₂O and ethyl acetateand vigorously stirred for 15 min. The mixture is then added to theseparatory funnel and the organic layer is collected. The aqueous layeris then extracted 3× with ethyl acetate. The combined organic layers arewashed with brine, dried with Na₂SO₄, and concentrated in vacuo.3-(2-Methyl-propane-2-sulfinylamino)-3-phenyl-propionic acid methylester is obtained as a clear colourless solid (102% yield); ES-MS(MH⁺)=284.1; ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 7.35-7.23 (m, 5H), 5.59(d, 1H, 6.1 Hz), 4.63 (m, 1H), 3.54 (s, 3H), 3.04-2.99 (m, 1H),2.80-2.74 (m, 1H), 1.06 (s, 9H).

Step C: 3-(2-Methyl-propane-2-sulfinylamino)-3-phenyl-propionic acidmethyl ester (1.73 mmol, 1 eq) is dissolved in 10 mL methanol (J. Org.Chem., 2002, 67, 7819-7832). A solution of HCl in dioxane (4 M, 10 mL)is added. The solution is stirred at room temperature for 45 min andconcentrated in vacuo. 3-Amino-3-phenyl-propionic acid methyl esterhydrochloride is obtained as yellow viscous oil (135% crude product);ES-MS (MH⁺)=181.1.

Step D: 3-Amino-3-phenyl-propionic acid methyl ester hydrochloride (1.3mmol, 1 eq), benzene-1,2-dicarbaldehyde (0.8 eq) and glacial acid (15eq) are dissolved in dichloromethane and refluxed for 2 h (J. Chem.Soc., Chem Commun 1985, 1183). The mixture is concentrated in vacuo andpartitioned between dichloromethane and water. The organic phase isdried over Na₂SO₄, filtered and concentrated in vacuo.3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid methylester is obtained as a brown solid (83% yield); ES-MS (MH⁺)=296.2;¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 7.73-7.30 (m, 9H), 5.82-5.78 (m, 1H),4.54 (d, 1H, 17.4 Hz), 4.14 (d, 1H, 17.4 Hz), 3.57 (s, 3H), 3.31-3.28(m, 2H).

Step E: 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acidmethyl ester (0.5 mmol, 1 eq) is dissolved in 8 mL 1 M NaOH/MeOH (25%V/V) and stirred at room temperature for 2 h. The solution is acidifiedwith 1 M HCl and extracted with dichloromethane. The organic phase isdried over Na₂SO₄, filtered and concentrated in vacuo.3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid is obtainedas red-orange residue (81% yield); ES-MS (MH⁺)=282.2.

Step F: 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid(0.42 mmol, 1 eq), 2-amino pyridine (1.5 eq), HBTU[2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphat],(1.5 eq) and N-ethyl diisopropylamine (1.5 eq) are suspended inchloroform and reacted in the microwave (90 min, 120° C., EmrysOptimizer). The resulting mixture is partitioned between chloroform andwater. The organic phase is dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product is dissolved in DMSO and purified by prep.LC/MS (reversed phase).3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide(“A1”) is obtained as brown solid (36% yield); ES-MS (MH⁺)=358.2; ¹H-NMR(DMSO-d₆, 400 MHz): δ [ppm] 10.72 (s, 1H), 8.29 (d, 1H, 4.8 Hz), 7.97(d, 1H, 8.3 Hz), 7.73-7.27 (m, 10H), 7.08-7.05 (m, 1H), 5.95-5.92 (m,1H), 4.62 (d, 1H, 17.5 Hz), 4.18 (d, 1H, 17.5 Hz), 3.39-3.32 (m, 2H).

The following compounds are obtained analogously

N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-thiophene-2-yl-propionamide(“A2”)

ES-MS (MH⁺)=442.3;3-Furan-3-yl-3-(1-oxo-1-dihydro-isoindole-yl)-N-pyridine-yl-propionamide(“A3”)

ES-MS (MH⁺)=448.2;N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide(“A4”)

ES-MS (MH⁺)=386.4;N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-thiophene-2-yl-propionamide(“A5”)

ES-MS (MH⁺)=378.3;N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide(“A6”)

ES-MS (MH⁺)=386.3;3-(4-Fluoro-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“A7”)

ES-MS (MH⁺) 390.5;N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide(“A8”)

ES-MS (MH⁺)=406.2;N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-yl)-3-thiophene-2-yl-propionamide(“A9”)

ES-MS (MH⁺)=384.4;3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-propionamide(“A10”)

ES-MS (MH⁺)=438.0; ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 12.28 (br, s, 1H),7.67 (d, 1H, 7.5 Hz), 7.59-7.44 (m, 4H), 7.17 (d, 1H, 3.6 Hz), 6.98 (d,1H, 1.9 Hz), 6.94-6.88 (m, 2H), 5.86 (dd, 1H, 8.7/6.9 Hz), 4.57 (d, 1H,17.4 Hz), 4.18 (d, 1H, 17.4 Hz), 3.98 (quart., 2H, 6.7 Hz), 3.75 (s,3H), 3:38-3.27 (m, 2H (known from TFA exchange spectrum)), 1.30 (t, 3H,7.0 Hz);

3-(4-Fluoro-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“A11”)

ES-MS (MH⁺)=390.4;3-(4-Fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide(“A12”)

ES-MS (MH⁺)=376.2;N-(4-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide(“A13”)

ES-MS (MH⁺)=386.5;3-Benzo[1,2,5]thiadiazole-5-yl-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide(“A14”)

ES-MS (MH⁺)=416.0; ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.76 (s, 1H),8.31-8.30 (m, 1H), 8.13 (s, 1H), 8.08 (d, 1H, 9.2 Hz), 7.97, (d, 1H, 8.3Hz), 7.74-7.70 (m, 3H), 7.62-7.57 (m, 2H), 7.51-7.48 (m, 1H), 7.10-7.07(m, 1H), 6.11-6.08 (m, 1H), 4.66 (d, 1H, 17.4 Hz), 4.29 (d, 1H, 17.4Hz), 3.59-3.35 (m, 2H);

3-(4-Fluoro-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)propionamide(“A15”)

ES-MS (MH⁺)=390.4;3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-pyridine-3-yl-N-pyridine-2-yl-propionamide(“A16”)

ES-MS (MH⁺)=358.2; ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.72 (s, 1H),8.29 (d, 1H, 4.8 Hz), 7.97 (d, 1H, 8.3 Hz), 7.73-7.27 (m, 10H),7.08-7.05 (m, 1H), 5.95-5.92 (m, 1H), 4.62 (d, 1H, 17.5), 4.18 (d, 1H,17.5 Hz), 3.39-3.32 (m, 2H);

3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide(“A17”)

ES-MS (MH⁺)=358.2. EXAMPLE 2 Preparation ofN-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B2”)

Step A: 3,4,5-Trimethoxy benzaldehyde (10 mmol, 1 eq), malonic acid (1eq) and ammonium acetate (1.3 eq) are suspended in EtOH and refluxed for16 h (Tetrahedron, 58 (2002) 7449-7461). Upon cooling to roomtemperature a white precipitate is formed. The mixture is concentratedin vacuo and the white solid is partitioned between EtOAc and diluteaqueous HCl (pH 2). The aqueous phase is concentrated in vacuo.3-Amino-3-(3,4,5-trimethoxy-phenyl)propionic acid (crude product) isobtained as a white solid (51% yield); ES-MS (MH⁺)=239.0 (M-NH₂).

Step B: 3-Amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3.66 mmol, 1eq), benzene-1,2-dicarbaldehyde (1 eq) and acetic acid (16 eq) aresuspended in dichloromethane and refluxed for 2 h. The filtrate isconcentrated in vacuo, dissolved in DCM and extracted with water. Theorganic phase is reduced under vacuum. The resulting oil is suspended in1 M NaOH and stirred for 30 min at room temperature. The solution iswashed with EtOAc and the aqueous phase is acidified with 1 M HCl (pH 2)and extracted with EtOAc. The organic phase is reduced under vacuum,dissolved in DCM and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resinis added. The suspension is shaken at rt for 16 h. The filtrate isconcentrated in vacuo, dissolved in DMSO and purified by prep. LC/MS(reversed phase).3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionicacid is obtained as a clear colourless film (20% yield); ES-MS(MH⁺)=372.0; mp. 162-164° C.; ¹H-NMR (DMSO-d₆, 300 MHz): δ [ppm] 12.37(br s, 1H), 7.69 (d, 1H, 7.6 Hz), 7.62-7.45 (m, 3H), 6.70 (s, 2H), 5.68(t, 1H, 7.9 Hz); 4.53 (d, 1H, 17.9 Hz), 4.20 (d, 1H, 17.9 Hz), 3.76 (s,6H), 3.63 (s, 3H), 3.14 (d, 2H, 7.9 Hz).

Step C: synthesis as for step F of example 1. The crude product ispurified by flash chromatography (petrol ether/EtOAc, Si60).N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)propionamide(“B2”) is obtained as white powder (19% yield); ES-MS (MH⁺)=482.0; mp.214° C. (dec); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.85 (s, 1H), 8.34(d, 1H, 2.6 Hz), 8.00 (d, 1H, 9.1 Hz), 7.83 (dd, 1H, 9.1/2.6 Hz), 7.67(d, 1H, 7.5 Hz), 7.58-7.56 (m, 2H), 7.49-7.45 (m, 1H), 6.70 (s, 2H),5.83 (dd, 1H, 8.8/7.1 Hz), 4.58 (d, 1H, 17.5 Hz), 4.22 (d, 1H, 17.5 Hz),3.76 (s, 6H), 3.63 (s, 3H), 3.36-3.23 (m, 2H).

Enantiomers were separated by SFC (method A).

The following compounds are obtained analogously

(+)-N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“C1”)

ES-MS (MH⁺)=482.0; t_(R)=2.18 min (method A) α_(D) ²⁰=+2.6° (c=0.06 inCHCl₃);

(−)-N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“C2”)

ES-MS (MH⁺)-482.0; t_(R)=1.93 min (method A);

N-(5-Chloro-pyridine-5-yl)-3-(2,3-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C3”)

ES-MS (MH⁺)=452.0;(+)-N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C4”)

ES-MS (MH⁺)=466.5; t_(R)=3.47 min (method B);

(−)-N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C5”)

ES-MS (MH⁺)=466.5; t_(R)=2.46 min (method B);

3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide(“C6”)

ES-MS (MH⁺)=432.2;3-(4-Ethoxy-3-methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C7”)

ES-MS (MH⁺)=446.6;3-(4-Ethoxy-3-methoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C8”)

ES-MS (MH⁺)=446.6;3-(4-Ethoxy-3-methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C9”)

ES-MS (MH⁺)=446.6;3-(4-Ethoxy-3-methoxy-phenyl)-N-(4-methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C10”)

ES-MS (MH⁺)=452.3;{2-[3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionylamino]-thiazole-4-yl}-aceticacid ethyl ester (“C11”)

ES-MS (MH⁺)=524.0; ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 12.33 (s, 1H),7.67-7.57 (m, 4H), 6.97-6.86 (m, 4H), 5.84 (dd, 1H, 8.7/7.1 Hz), 4.56(d, 1H, 17.4 Hz), 4.16 (d, 1H, 17.4 Hz), 4.07 (quart., 2H, 7.0 Hz), 3.97(quart., 2H, 7.0 Hz), 3.74 (s, 3H), 3.66 (s, 2H), 3.34-3.26 (m, 2H),1.29 (t, 3H, 7.0 Hz), 1.17 (t, 3H, 7.0 Hz);

3-(2,3-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-propionamide(“C12”)

ES-MS (MH⁺)=424.0;2-[3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester (“C13”)

ES-MS (MH⁺)=510.0;3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyrazine-2-yl-propionamide(“C14”)

ES-MS (MH⁺)=433.0; ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.97 (br, s, 1H),9.21 (d, 1H, 1.2 Hz), 8.38 (dd, 1H, 2.5/1.4 Hz), 8.34 (d, 1H, 2.5 Hz),7.67 (d, 1H, 7.5 Hz), 7.60-7.57 (m, 2H), 7.50-7.45 (m, 1H), 7.00 (d, 1H,1.6 Hz), 6.94-6.89 (m, 2H), 5.87 (dd, 1H, 9.0/6.7 Hz), 4.59 (d, 1H, 17.5Hz), 4.17 (d, 1H, 17.5 Hz), 3.98 (quart., 2H, 6.9 Hz), 3.76 (s, 3H),3.39-3.26 (m, 2H), 1.3 (t, 3H, 6.9 Hz);

N-(2,6-Dimethyl-pyrimidine-4-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C15”)

ES-MS (MH⁺)=461.0; ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 11.03 (s, 1H),7.73 (d, 2H, 6.4 Hz), 7.65-7.63 (m, 2H), 7.57-7.50 (m, 1H), 7.03 (d, 1H,1.8 Hz), 6.99-6.91 (m, 2H), 5.90 (dd, 1H, 9.0/6.6 Hz), 4.62 (d, 1H, 17.5Hz), 4.22 (d, 1H, 17.5 Hz), 4.03 (quart., 2H, 7.0 Hz), 3.80 (s, 3H),3.44-3.26 (m, 2H), 2.52 (s, 3H), 2.38 (s, 3H), 1.37-1.30 (m, 3H);

3-(4-Ethoxy-3-methoxy-phenyl)-N-(1-methyl-1H-pyrazole-3-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C16”)

ES-MS (MH⁺)=435.0; ¹NMR (DMSO-d₆, 400 MHz): δ [ppm] 10.59 (s, 1H), 7.67(d, 1H, 7.5 Hz), 7.59-7.57 (m, 2H), 7.51-7.46 (m, 2H), 6.97 (d, 1H, 1.8Hz), 6.92-6.85 (m, 2H), 6.34 (d, 1H, 2.2 Hz), 5.85-5.81 (m, 1H), 4.57(d, 1H, 17.5 Hz), 4.17 (d, 1H, 17.5 Hz), 3.97 (quart., 2H, 7.0 Hz), 3.76(s, 3H), 3.71 (s, 3H), 3.21 (dd, 1H, 14.5/6.9 Hz), 3.11-3.06 (m, 1H),1.34-1.24 (m, 3H);

N-(1H-Benzimidazole-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C17”)

ES-MS (MH⁺)=471.0; ¹NMR (DMSO-d₆, 500 MHz): δ [ppm] 7.67 (d, 1H, 7.6Hz), 7.58 (d, 2H, 4.0 Hz), 7.50-7.41 (m, 3H), 7.11-7.09 (m, 2H), 7.02(d, 1H, 1.3 Hz), 6.95-6.91 (m, 2H), 5.92-5.88 (m, 1H), 4.62 (d, 1H, 17.5Hz), 4.21 (d, 1H, 17.5 Hz), 3.98 (quart., 2H, 7.0 Hz), 3.77 (s, 3H),3.38-3.25 (m, 2H), 1.30 (t, 3H, 7.0 Hz);

3-(4-Ethoxy-3-methoxy-phenyl)-N-isoxazole-3-yl-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C18”)

ES-MS (MH⁺)=422.0;3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyrimidine-4-yl-propionamide(“C19”)

ES-MS (MH⁺)=433.0; ¹NMR (DMSO-d₆, 400 MHz): δ [ppm] 11.05 (s, 1H), 8.79(s, 1H), 8.52 (d, 1H, 5.8 Hz), 7.89-7.87 (m, 1H), 7.59 (d, 1H, 7.6 Hz),7.53-7.49 (m, 2H), 7.43-7.37 (m, 1H), 6.91 (d, 1H, 1.7 Hz), 6.86-6.80(m, 2H), 5.78 (dd, 1H, 9.0/6.7 Hz), 4.89 (d, 1H, 17.4 Hz), 4.09 (d, 1H,17.4 Hz), 3.90 (quart., 2H, 7.0 Hz), 3.67 (s, 3H), 3.34-3.18 (m, 2H),1.24-1.16 (m, 3H);

N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3-trifluoromethoxy-phenyl)-propionamide(“C20”)

ES-MS (MH⁺)=476.0; ¹NMR (DMSO-d₆, 400 MHz): δ [ppm] 10.91 (s, 1H), 8.35(d, 1H, 2.5 Hz), 8.00 (d, 1H, 9.0 Hz), 7.83 (dd, 1H, 9.0/2.7 Hz), 7.68(d, 1H, 7.6 Hz), 7.60-7.26 (m, 7H), 5.91 (dd, 1H, 9.1/6.6 Hz), 4.63 (d,1H, 17.5 Hz), 4.27 (d, 1H, 17.5 Hz), 3.46-3.24 (m, 2H);

3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyrimidine-2-yl-propionamide(“C21”)

ES-MS (MH⁺)=433.2;3-(4-Ethoxy-3-methoxy-phenyl)-N-(5-methyl-isoxazole-3-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C22”)

ES-MS (MH⁺)=436.0.N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“C23”)

Pharmacological Data

TABLE 1 Glucokinase Activation Assay fold activation EC₅₀ compound nr.(human) (human) “B7” B “B6” C “B5” C “B2” B “C5” C “C4” C “C3” C “C1” B“C23” C fold activation/EC₅₀: 10 nM-1 μM = A 1 μM-10 μM = B >10 μM = C

The following examples relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient according to the inventionand 5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient according to the inventionwith 100 g of soya lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient according to theinvention, 9.38 g of NaH2PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient according to the invention, 4 kgof lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is pressed to give tablets in a conventional mannerin such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient according to the invention are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of an active ingredient according to the invention in60 l of bidistiiled water is sterile filtered, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹ denotes A, Ar or Het, R², R^(2′), R^(2″) each, independentlyof one another, denote H, A, OA or Hal, R³ denotes Het, R⁴, R⁵ denote H,R⁶ denotes H, A, Ar or Het, R⁷, R⁸ denote H or R⁷ and R⁸ together denote═O, R⁹, R¹⁰, R¹¹ each, independently of one another, denote H, A, Ar orHet, A denotes unbranched or branched alkyl having 1-10 C atoms, inwhich one or two non-adjacent CH₂ groups may be replaced by O, S, SO,SO₂, NH, NA′, NAr, NHet and/or by —CH═CH— groups and/or in addition 1-7H atoms may be replaced by OH, F, Cl, Br, ═S, ═NR⁹ and/or ═O or denotescycloalkyl having 3-7 C atoms, which is unsubstituted or mono-, di- ortrisubstituted by ═O, F, Cl, OH, OA′, OAr′, OHet′, SO_(n)A′, SO_(n)Ar′,SO_(n)Het′, NH₂, NHA′, NA′₂, NHAr′ and/or NHHet′, A′ denotes unbranchedor branched alkyl having 1-6 C atoms in which 1-7 H atoms may bereplaced by F and/or Cl, Alk denotes unbranched or branched alkylenehaving 1, 2, 3 or 4 C atoms, Ar denotes phenyl, naphthyl or biphenyl,each of which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by A, Hal, (CR⁹R¹⁰)_(m)Ar′, (CR⁹R¹⁰)_(m)Het′,O(CR⁹R¹⁰)_(m)R¹¹, S(O)_(n)R⁹, NH₂, NHA′, NA′₂, NHAr′, NHHet′, NO₂, CN,COOR⁹, CON(R⁹R¹⁰)₂, NR⁹COR¹⁰, NR⁹CON(R¹⁰R¹¹)₂, NR⁹SO_(n)R¹⁰, COR⁹, SO₃H,SO_(n)N(R⁹R¹⁰)₂, O-Alk-N(R⁹R¹⁰)₂, O(CR⁹R¹⁰)_(m)CON(R⁹R¹⁰)₂,O-Alk-NR⁹COR¹⁰, O(CR⁹R¹⁰)_(m)Het′, O(CR⁹R¹⁰)_(m)Ar′,S(O)_(n)(CR⁹R¹⁰)_(m)Het′ and/or S(O)_(n)(CR⁹R¹⁰)_(m)Ar′, Het denotes amono- or bicyclic saturated, unsaturated or aromatic heterocycle having1 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted byHal, A, (CR⁹R¹⁰)_(m)Ar′, (CR⁹R¹⁰)_(m)Het′, O(CR⁹R¹⁰)_(m)Ar′,O(CR⁹R¹⁰)_(m)Het′, (CR⁹R¹⁰)_(m)cycloalkyl, (CR⁹R¹⁰)_(m)OR¹²,(CR⁹R¹⁰)_(m)N(R¹¹)₂, NO₂, CN, (CR⁹R¹⁰)_(m)COOR¹¹, O(CR⁹R¹⁰)_(m)COOR¹¹,(CR⁹R¹⁰)_(m)CON(R¹¹)₂, (CR⁹R¹⁰)_(m)CONR¹¹N(R⁹R¹⁰)₂,O(CR⁹R¹⁰)_(m)CON(R¹¹)₂, O(CR⁹R¹⁰)_(m)CONR¹¹N(R⁹R¹⁰)₂,(CR⁹R¹⁰)_(m)NR¹¹COA, NR⁹CON(R¹⁰R¹¹)₂, (CR⁹R¹⁰)_(m)NR¹¹SO₂A, COR⁹,SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, ═S, ═NR² and/or ═O (carbonyl oxygen), Ar′denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted ormono-, di- or trisubstituted by Hal, A, OR⁹, N(R⁹R¹⁰)₂, NO₂, CN, COOR⁹,CON(R⁹R¹⁰)₂, NR⁹COA, NR⁹CON(R¹⁰R¹¹)₂, NR⁹SO₂A, COR⁹, SO₂N(R⁹R¹⁰)₂,S(O)_(n)A, (CR⁹R¹⁰)_(m)COOR¹¹ and/or O(CR⁹R¹⁰)_(m)COOR¹¹, Het′ denotes amono- or bicyclic saturated, unsaturated or aromatic heterocycle having1 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted byHal, A, OR⁹, N(R⁹R¹⁰)₂, NO₂, CN, COOR⁹, CON(R⁹R¹⁰)₂, NR⁹COA, NR⁹SO₂A,COR⁹, SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, ═S, ═NR⁹ and/or ═O (carbonyl oxygen), Haldenotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, n denotes 0, 1 or 2,and pharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, excluding the compounds selected fromthe groupN-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide,3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide,N-(5-Bromo-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(4-fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(3,4-Dimethoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide,3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridin-2-yl-3-thiophene-2-yl-propionamide,3-(4-Methoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,3-(4-Methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(3,4-Dimethoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide,N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide.2. Compounds according to claim 1 in which R¹ denotes Ar or Het, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 3. Compounds according to claim 1 inwhich R², R^(2′), R^(2″) denote H, and pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios. 4.Compounds according to claim 1 in which R⁶ denotes H, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 5. Compounds according to claim 1 inwhich R⁷, R⁸ denote H, and pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios. 6.Compounds according to claim 1 in which R⁹, R¹⁰ denote H, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 7. Compounds according to claim 1 inwhich R¹¹ denotes H or A, and pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios. 8.Compounds according to claim 1 in which A denotes unbranched or branchedalkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by Fand/or Cl, and pharmaceutically usable salts and stereoisomers thereof,including mixtures thereof in all ratios.
 9. Compounds according toclaim 1 in which Ar denotes phenyl, which is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted by A, Hal and/or O(CR⁹R¹⁰)_(m)R¹¹,and pharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 10. Compounds according to claim 1 inwhich Het denotes a mono- or bicyclic unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may be mono-, di-or trisubstituted by Hal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 11. Compounds according to claim 1 inwhich Het denotes pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyrrolyl, furanyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, benzo[1,3]dioxolyl, benzimidazolyl,benzo[1,2,5]thiadiazolyl, indolyl, indazolyl, which may be mono-, di- ortrisubstituted by Hal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹, and pharmaceuticallyusable salts and stereoisomers thereof, including mixtures thereof inall ratios.
 12. Compounds according to claim 1 in which R¹ denotes Ar orHet, R², R^(2′), R^(2″) denote H, R³ denotes Het, R⁴, R⁵ denote H, R⁶denotes H, R⁷, R⁸ denote H, R⁹, R¹⁰ denote H, R¹¹ denotes H or A, Adenotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 Hatoms may be replaced by F and/or Cl, Ar denotes phenyl, which isunsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Haland/or O(CR⁹R¹⁰)_(m)R¹¹, Het denotes a mono- or bicyclic unsaturated oraromatic heterocycle having 1 to 4 N, O and/or S atoms, which may bemono-, di- or trisubstituted by Hal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹, Haldenotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, and pharmaceuticallyusable salts and stereoisomers thereof, including mixtures thereof inall ratios.
 13. Compounds according to claim 1 selected from the groupno. name and/or structure “A1”3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-

propionamide “A2”N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-thiophene-2-yl-propionamide “A3”3-Furan-3-yl-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridineyl-propionamide “A4”N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-p-tolyl-propionamide “A5”N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-thiophene-2-yl-propionamide “A6”N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-p-tolyl-propionamide “A7”3-(4-Fluoro-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3dihydro-isoindole-2-yl)-propionamide “A8”N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-p-tolyl-propionamide “A9”N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-thiophene-2-yl-propionamide “A10”3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindo

2-yl)-N-thiazole-2-yl-propionamide “A11”3-(4-Fluoro-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3dihydro-isoindole-2-yl)-propionamide “A12”3-(4-Fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-Npyridine-2-yl-propionamide “A13”N-(4-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-p-tolyl-propionamide “A14”3-Benzo[1,2,5]thiadiazole-5-yl-3-(1-oxo-1,3-dihydro-isoindol2-yl)-N-pyridine-2-yl-propionamide “A15”3-(4-Fluoro-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3dihydro-isoindole-2-yl)-propionamide “A16”3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-pyridine-3-yl-N-pyridine-2-yl-propionamide “A17”3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-

propionamide “C1”(+)-N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindol2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide “C2”(−)-N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindol2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide “C3”N-(5-Chloro-pyridine-2-yl)-3-(2,3-dimethoxy-phenyl)-3-(1-ox

1,3-dihydro-isoindole-2-yl)-propionamide “C4”(+)-N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-pheny

3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C5”(−)-N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-pheny

3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C6”3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindo

2-yl)-N-pyridine-2-yl-propionamide “C7”3-(4-Ethoxy-3-methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-

(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C8”3-(4-Ethoxy-3-methoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-

(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C9”3-(4-Ethoxy-3-methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-

(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C10”3-(4-Ethoxy-3-methoxy-phenyl)-N-(4-methyl-thiazole-2-yl)-

(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C11”{2-[3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionylamino]-thiazole-4-yl}-acetic acid et

ester “C12” 3-(2,3-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-y

N-thiazole-2-yl-propionamide “C13”2-[3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionylamino]-thiazole-4-carboxylic acid et

ester “C14” 3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindo

2-yl)-N-pyrazine-2-yl-propionamide “C15”N-(2,6-Dimethyl-pyrimidine-4-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C16”3-(4-Ethoxy-3-methoxy-phenyl)-N-(1-methyl-1H-pyrazole-3-y3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C17”N-(1H-Benzimidazole-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C18”3-(4-Ethoxy-3-methoxy-phenyl)-N-isoxazole-3-yl-3-(1-oxo-1,dihydro-isoindole-2-yl)-propionamide “C19”3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindo

2-yl)-N-pyrimidine-4-yl-propionamide “C20”N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2yl)-3-(3-trifluoromethoxy-phenyl)-propionamide “C21”3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindo

2-yl)-N-pyrimidine-2-yl-propionamide “C22”3-(4-Ethoxy-3-methoxy-phenyl)-N-(5-methyl-isoxazole-3-yl)-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide “C23”N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide

indicates data missing or illegible when filed

and pharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 14. Process for the preparation ofcompounds of the formula I according to claim 1 and pharmaceuticallyusable salts and stereoisomers thereof, characterised in that a compoundof the formula II

in which L denotes Cl, Br, I or a free or reactively functionallymodified OH group and R¹, R², R^(2′), R^(2″), R⁴, R⁵, R⁶, R⁷ and R⁸ havethe meanings indicated in claim 1, is reacted with a compound of theformula IIIH₂N—R³  III in which R³ has the meanings indicated in claim 1, and/or abase or acid of the formula I is converted into one of its salts. 15.Medicaments comprising at least one compound of formula I

in which R¹ denotes A, Ar or Het, R², R^(2′), R^(2″) each, independentlyof one another, denote H, A, OA or Hal, R³ denotes Het, R⁴, R⁵ denote H,R⁶ denotes H, A, Ar or Het, R⁷, R⁸ denote H or R⁷ and R⁸ together denote═O, R⁹, R¹⁰, R¹¹ each, independently of one another, denote H, A, Ar orHet, A denotes unbranched or branched alkyl having 1-10 C atoms, inwhich one or two non-adjacent CH₂ groups may be replaced by O, S, SO,SO₂, NH, NA′, NAr, NHet and/or by —CH═CH— groups and/or in addition 1-7H atoms may be replaced by OH, F, Cl, Br, ═S, ═NR⁹ and/or ═O or denotescycloalkyl having 3-7 C atoms, which is unsubstituted or mono-, di- ortrisubstituted by ═O, F, Cl, OH, OA′, OAr′, OHet′, SO_(n)A′, SO_(n)Ar′,SO_(n)Het′, NH₂, NHA′, NA′₂, NHAr′ and/or NHHet′, A′ denotes unbranchedor branched alkyl having 1-6 C atoms in which 1-7 H atoms may bereplaced by F and/or Cl, Alk denotes unbranched or branched alkylenehaving 1, 2, 3 or 4 C atoms, Ar denotes phenyl, naphthyl or biphenyl,each of which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by A, Hal, (CR⁹R¹⁰)_(m)Ar′, (CR⁹R¹⁰)_(m)Het′,O(CR⁹R¹⁰)_(m)R¹¹, S(O)_(n)R⁹, NH₂, NHA′, NA′₂, NHAr′, NHHet′, NO₂, CN,COOR⁹, CON(R⁹R¹⁰)₂, NR⁹COR¹⁰, NR⁹CON(R¹⁰R¹¹)₂, NR⁹SO_(n)R¹⁰, COR⁹, SO₃H,SO_(n)N(R⁹R¹⁰)₂, O-Alk-N(R⁹R¹⁰)₂, O(CR⁹R¹⁰)_(m)CON(R⁹R¹⁰)₂,O-Alk-NR⁹COR¹⁰, O(CR⁹R¹⁰)_(m)Het′, O(CR⁹R¹⁰)_(m)Ar′,S(O)_(n)(CR⁹R¹⁰)_(m)Het′ and/or S(O)_(n)(CR⁹R¹⁰)_(m)Ar′, Het denotes amono- or bicyclic saturated, unsaturated or aromatic heterocycle having1 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted byHal, A, (CR⁹R¹⁰)_(m)Ar′, (CR⁹R¹⁰)_(m)Het′, O(CR⁹R¹⁰)_(m)Ar′,O(CR⁹R¹⁰)_(m)Het′, (CR⁹R¹⁰)_(m)cycloalkyl, (CR⁹R¹⁰)_(m)OR¹²,(CR⁹R¹⁰)_(m)N(R¹¹)₂, NO₂, CN, (CR⁹R¹⁰)_(m)COOR¹¹, O(CR⁹R¹⁰)_(m)COOR¹¹,(CR⁹R¹⁰)_(m)CON(R¹¹)₂, (CR⁹R¹⁰)_(m)CONR¹¹N(R⁹R¹⁰)₂,O(CR⁹R¹⁰)_(m)CON(R¹¹)₂, O(CR⁹R¹⁰)_(m)CONR¹¹N(R⁹R¹⁰)₂,(CR⁹R¹⁰)_(m)NR¹¹COA, NR⁹CON(R¹⁰R¹¹)₂, (CR⁹R¹⁰)_(m)NR¹¹SO₂A, COR⁹,SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, ═S, ═NR² and/or ═O (carbonyl oxygen), Ar′denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted ormono-, di- or trisubstituted by Hal, A, OR⁹, N(R⁹R¹⁰)₂, NO₂, CN, COOR⁹,CON(R⁹R¹⁰)₂, NR⁹COA, NR⁹CON(R¹⁰R¹¹)₂, NR⁹SO₂A, COR⁹, SO₂N(R⁹R¹⁰)₂,S(O)_(n)A, (CR⁹R¹⁰)_(m)COOR¹¹ and/or O(CR⁹R¹⁰)_(m)COOR¹¹, Het′ denotes amono- or bicyclic saturated, unsaturated or aromatic heterocycle having1 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted byHal, A, OR⁹, N(R⁹R¹⁰)₂, NO₂, CN, COOR⁹, CON(R⁹R¹⁰)₂, NR⁹COA, NR⁹SO₂A,COR⁹, SO₂N(R⁹R¹⁰)₂, S(O)_(n)A, ═S, ═NR⁹ and/or ═O (carbonyl oxygen), Haldenotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, n denotes 0, 1 or 2,and/or pharmaceutically usable salts and stereoisomers thereof,including mixtures thereof in all ratios, and optionally excipientsand/or adjuvants.
 16. Medicaments according to claim 15, comprising atleast one compound of formula I, in which R¹ denotes Ar or Het, and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 17. Medicaments according to claim 15, comprising at leastone compound of formula I, in which R², R^(2′), R^(2″) denote H, and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 18. Medicaments according to claim 15, comprising at leastone compound of formula I, in which R⁶, R⁷, R⁸, R⁹, R¹⁰ denote H, and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 19. Medicaments according to claim 15, comprising at leastone compound of formula I, in which R¹¹ denotes H or A, and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 20. Medicaments according to claim 15, comprising at leastone compound of formula I, in which A denotes unbranched or branchedalkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by Fand/or Cl, and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios, and optionallyexcipients and/or adjuvants.
 21. Medicaments according to claim 15,comprising at least one compound of formula I, in which Ar denotesphenyl, which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by A, Hal and/or O(CR⁹R¹⁰)_(m)R¹¹, and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 22. Medicaments according to claim 15, comprising at leastone compound of formula I, in which Het denotes a mono- or bicyclicunsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be mono-, di- or trisubstituted by Hal, A and/or(CR⁹R¹⁰)_(m)COOR¹¹, and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.
 23. Medicaments according toclaim 15, comprising at least one compound of formula I, in which Hetdenotes pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl, furanyl,thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, isoxazolyl, benzo[1,3]dioxolyl, benzimidazolyl,benzo[1,2,5]thiadiazolyl, indolyl, indazolyl, which may be mono-, di- ortrisubstituted by Hal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹, and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 24. Medicaments according to claim 15, comprising at leastone compound of formula I, in which R¹ denotes Ar or Het, R², R^(2′),R^(2″) denote H, R³ denotes Het, R⁴, R⁵ denote H, R⁶ denotes H, R⁷, R⁸denote H, R⁹, R¹⁰ denote H, R¹¹ denotes H or A, A denotes unbranched orbranched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replacedby F and/or Cl, Ar denotes phenyl, which is unsubstituted or mono-, di-,tri-, tetra- or pentasubstituted by A, Hal and/or O(CR⁹R¹⁰)_(m)R¹¹, Hetdenotes a mono- or bicyclic unsaturated or aromatic heterocycle having 1to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted byHal, A and/or (CR⁹R¹⁰)_(m)COOR¹¹, Hal denotes F, Cl, Br or I, m denotes0, 1, 2, 3 or 4 and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios, and optionallyexcipients and/or adjuvants.
 25. Medicaments according to claim 15,comprising at least one compound selected from:3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide,N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-thiophene-2-yl-propionamide,3-Furan-3-yl-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide,N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide,N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-thiophene-2-yl-propionamide,N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide,3-(4-Fluoro-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide,N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-thiophene-2-yl-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-propionamide,3-(4-Fluoro-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide,N-(4-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide,3-Benzo[1,2,5]thiadiazole-5-yl-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide,3-(4-Fluoro-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-pyridine-3-yl-N-pyridine-2-yl-propionamide,3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide,(+)-N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,(−)-N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(2,3-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,(+)-N-(5-Chloro)-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,(−)-N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-(6-methyl-Pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-(4-methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,{2-[3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionylamino]-thiazole-4-yl}-aceticacid ethyl ester,3-(2,3-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-propionamide,2-[3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester,3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyrazine-2-yl-propionamide,N-(2,6-Dimethyl-pyrimidine-4-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-(1-methyl-1H-pyrazole-3-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(1H-Benzimidazole-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-isoxazole-3-yl-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyrimidine-4-yl-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3-trifluoromethoxy-phenyl)-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyrimidine-2-yl-propionamide,3-(4-Ethoxy-3-methoxy-phenyl)-N-(5-methyl-isoxazole-3-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(5-Chloro-pyridine-2-yl)-3-(4-ethoxy-3-methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide,N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B1”),N-(5-Chloro-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B2”),3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide(“B3”),3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B4”),N-(5-Bromo-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B5”),N-(5-Chloro-pyridine-2-yl)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B6”),N-(5-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B7”),N-(5-Chloro-pyridine-2-yl)-3-(4-fluoro-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B8”),3-(3,4-Dimethoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B9”),N-(5-Bromo-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-p-tolyl-propionamide(“B10”),3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-pyridin-2-yl-3-thiophene-2-yl-propionamide(“B11”),3-(4-Methoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B12”),N-(6-Methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B13”),3-(4-Methoxy-phenyl)-N-(4-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B14”),3-(3,4-Dimethoxy-phenyl)-N-(6-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B15”),3-(4-Methoxy-phenyl)-N-(5-methyl-pyridine-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-propionamide(“B16”),3-(4-Methoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-N-pyridine-2-yl-propionamide(“B17”),N-(4-Methyl-thiazole-2-yl)-3-(1-oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B18”),3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-N-thiazole-2-yl-3-(3,4,5-trimethoxy-phenyl)-propionamide(“B19”).
 26. Method for the treatment of a disease or conditionresulting from underactivity of glucokinase or which can be treated byactivating glucokinase, said method comprising administering to apatient an effective amount of a medicament according to claim
 15. 27. Amethod according to claim 26, wherein the disease or condition isinsulin-dependent diabetes mellitus, non-insulin-dependent diabetesmellitus, obesity, neuropathy and/or nephropathy.
 28. A medicamentaccording to claim 15 further comprising at least one further medicamentactive ingredient.
 29. Set (kit) comprising separate packs of: (a) aneffective amount of a medicament according to claim 15 and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and (b) an effective amount of a furthermedicament active ingredient.